Risk Management and Mitigating Risk Opportunities for Opioid Prescribing.

All clinicians are ethically obliged to prescribe responsibly and cautiously to diminish the potential for opioid diversion and to help minimize the growth of the current opioid abuse epidemic. Podiatric physicians should establish procedures to better control and limit opioid prescription and develop analgesic regimens to treat pain. The main purpose and goal of this review is to present data congruent with clinical, medical, and legal reports for allowing an appreciation of the possibility of the risk assumed when ordering and prescribing opioids within the podiatric medical profession. First, the concept and process of risk management, illustrated using a root cause analysis approach, is introduced, and application of these principles specifically to opioid prescribing is presented. Then, several examples found in both the medical and legal literature documenting the reasons for opioid prescription risk are presented. Finally, mitigating strategies for safe opioid prescribing are offered so that mitigation of opioid harm can be possible and realized by the lower-extremity specialist. Risk management strategies and tools to mitigate opioid harm, lessen opioid adverse effects, and reduce opioid deaths are presented narratively and graphically.

An Appraisal of Opioid Treatment Agreements for the Podiatric Physician.

Opioid treatment agreements are written agreements between physicians and patients that represent strategies enumerating the risks associated with opioid medications. These opioid treatment agreements set expectations and obligations, as well as identify responsibilities for both patient and prescriber for opioid therapy. Some critics assert that these agreements are cumbersome and degrade the patient once they enter into these agreements. A systemic literature search and review using the Preferred Reporting Item for Systematic Reviews and Meta-Analyses (PRISMA) tool was used to find citations describing opioid treatment agreements and their use. Then eligible and appropriate citations were dissected and analyzed. Using the available federal and state opioid prescribing policies, best practice guidelines as well as positive aspects of reviewed literature citations and avoiding bias, degrading, or macroaggression language, a non-cumbersome opioid treatment agreement specific to podiatric medicine was created. A balance argument for the use of opioid treatment agreements to avoid opioid use disorder that is grounded in clinical literature and commentaries are presented. A one-page sensible opioid treatment agreement specific to podiatric medicine, which is similar to more complex cumbersome ones that are found in the literature, and that may be used as part of any podiatric procedural or surgical inform consent, was created and is presented for review. The perception of defending opioid treatment agreements as documents of disclosure to assist patients in their autonomy was offered. Building on the systemic review findings and concept of using elements of disclosure, a model for an analgesic treatment as a one-page informational document to enhance podiatric physicians to create a specific individual analgesic treatment agreement mirroring the scope of podiatric practices that can be incorporated into procedural and surgical inform consent documents was offered.

An Appraisal of Using Opioids in Patients with Opioid Use Disorder.

Podiatric physicians have come to realize that opioid use disorder (OUD) is a public health crisis causing morbidity, mortality, lost productivity, and legal cost in the United States. Opioid analgesics are efficient first-line pain relievers for acute and chronic lower-extremity pain syndrome. Perioperative pain management strategies have been proposed using opioid stewardship, but there are few standardized protocols to guide podiatric medical providers treating patients with OUD. First, we describe the pharmacology of therapeutic agents used as medications for addiction treatment for OUD and substance use disorder (SUD). Second, we offer criteria for selecting acute pain and perioperative management in patients with OUD and SUD per current medical literature. Finally, we review the literature applying opioid stewardship in the context of prescribing opioid analgesics in the presence of OUD and SUD. Three hypothetical clinical scenarios grounded in clinical-based literature are described with congruent data and founded guidelines. The first and second scenarios describe acute pain and perioperative management in patients with OUD receiving methadone and buprenorphine-naloxone, respectively. The third scenario describes acute pain and perioperative management in a patient with SUD receiving intravenous naltrexone. We hope that the lower-extremity specialist will appreciate that thoughtful management of acute perioperative pain among patients who receive medications for addiction treatment for OUD is critically important given the risks of destabilization during the perioperative period. The literature reveals the lack of rigorous evidence on acute pain management in patients who receive medication for OUD; however, some clinical evidence supports the practice of continuing methadone or buprenorphine for most patients during acute pain episodes.

Two mechanisms for direction selectivity in a model of the primate starburst amacrine cell.

In a recent study, visual signals were recorded for the first time in starburst amacrine cells of the macaque retina, and, as for mouse and rabbit, a directional bias observed in calcium signals was recorded from near the dendritic tips. Stimulus motion from the soma toward the tip generated a larger calcium signal than motion from the tip toward the soma. Two mechanisms affecting the spatiotemporal summation of excitatory postsynaptic currents have been proposed to contribute to directional signaling at the dendritic tips of starbursts: (1) a "morphological" mechanism in which electrotonic propagation of excitatory synaptic currents along a dendrite sums bipolar cell inputs at the dendritic tip preferentially for stimulus motion in the centrifugal direction; (2) a "space-time" mechanism that relies on differences in the time-courses of proximal and distal bipolar cell inputs to favor centrifugal stimulus motion. To explore the contributions of these two mechanisms in the primate, we developed a realistic computational model based on connectomic reconstruction of a macaque starburst cell and the distribution of its synaptic inputs from sustained and transient bipolar cell types. Our model suggests that both mechanisms can initiate direction selectivity in starburst dendrites, but their contributions differ depending on the spatiotemporal properties of the stimulus. Specifically, the morphological mechanism dominates when small visual objects are moving at high velocities, and the space-time mechanism contributes most for large visual objects moving at low velocities.

Postoperative Opioid-Prescribing Practice in Foot and Ankle Surgery.

BACKGROUND: Approximately 3,900 Americans die every month of opioid overdose. The total economic burden of the opioid epidemic is estimated to be more than $78 billion annually. We sought to determine whether postoperative opioid-prescribing practice variation exists in foot and ankle surgery. METHODS: We administered a voluntary, anonymous, online questionnaire consisting of six foot and ankle surgery scenarios followed by a demographics section. The purpose of the demographics section was to gather characteristics of podiatric foot and ankle surgeons. We invited podiatric foot and ankle surgeons practicing in the United States to complete the questionnaire via e-mail from the American Podiatric Medical Association's membership list. For each scenario, respondents selected the postoperative opioid(s) that they would prescribe at the time of surgery, as well as the dose, frequency, and number of "pills" (dosage units). We developed multiple linear regression models to identify associations between prescriber characteristics and two measures of opioid quantity: dosage units and morphine milligram equivalents. RESULTS: Eight hundred sixty podiatric foot and ankle surgeons completed the survey. The median number of dosage units never exceeded 30 regardless of the foot and ankle surgery. Years in practice correlated with reduction in dosage units at the time of surgery. Compared with the orthopedic community, podiatric foot and ankle surgeons prescribe approximately 25% less dosage units than orthopedic foot and ankle surgeons. CONCLUSIONS: Postoperative opioid-prescribing practice variation exists in foot and ankle surgery. Further research is warranted to determine whether additional education is needed for young surgeons.

Attitudes of eye health practitioners towards diagnostic tests and therapies for dry eye disease in Australasia.

INTRODUCTION: The diagnosis of dry eye is challenging for eye health practitioners (EHP) and recently, a variety of new diagnostic tests have emerged. This study assesses the attitudes of EHP to dry eye and testing and compares these with attitudes in 2003. METHODS: An electronic questionnaire was disseminated to EHP in Australasia between December 2020 to March 2021. Participants rated the likelihood that presenting symptoms/signs were associated with dry eye, the utility of diagnostic tests, the value of test characteristics, and their satisfaction with dry eye diagnostics. Qualitative responses were categorised into positive, negative, or neutral themes. RESULTS: 144 responses were received, with 117 (81.3%) from Australia and 27 (18.7%) from New Zealand. Posterior blepharitis was significantly more likely to be associated with dry eye than other factors (p < 0.01). Clinical history, fluorescein staining and FBUT were judged significantly more useful in diagnosing dry eye compared to other tests (p < 0.01). Test validity was judged significantly more important in choosing a test than other qualities. Qualitative attitudes towards dry eye presentations and diagnostic tests were positive in 42.2% and 24.3%, negative in 32.4% and 41.9%, and neutral in 25.5% and 33.8% respectively. CONCLUSIONS: The opinions of EHP regarding dry eye tests were variable, but most favour history and corneal staining for diagnosis. Patterns of responses were similar to that reported by Turner et al 16-years ago, however, there is a higher satisfaction with available tests and therapeutic options. There is a need to develop a consensus amongst real-world clinicians regarding an optimum diagnostic pathway for dry eye, particularly in relation to newer diagnostic tests.

Origins of direction selectivity in the primate retina.

From mouse to primate, there is a striking discontinuity in our current understanding of the neural coding of motion direction. In non-primate mammals, directionally selective cell types and circuits are a signature feature of the retina, situated at the earliest stage of the visual process. In primates, by contrast, direction selectivity is a hallmark of motion processing areas in visual cortex, but has not been found in the retina, despite significant effort. Here we combined functional recordings of light-evoked responses and connectomic reconstruction to identify diverse direction-selective cell types in the macaque monkey retina with distinctive physiological properties and synaptic motifs. This circuitry includes an ON-OFF ganglion cell type, a spiking, ON-OFF polyaxonal amacrine cell and the starburst amacrine cell, all of which show direction selectivity. Moreover, we discovered that macaque starburst cells possess a strong, non-GABAergic, antagonistic surround mediated by input from excitatory bipolar cells that is critical for the generation of radial motion sensitivity in these cells. Our findings open a door to investigation of a precortical circuitry that computes motion direction in the primate visual system.

Visual stimulation induces distinct forms of sensitization of On-Off direction-selective ganglion cell responses in the dorsal and ventral retina.

Experience-dependent modulation of neuronal responses is a key attribute in sensory processing. In the mammalian retina, the On-Off direction-selective ganglion cell (On-Off DSGC) is well known for its robust direction selectivity. However, how the On-Off DSGC light responsiveness dynamically adjusts to the changing visual environment is underexplored. Here, we report that On-Off DSGCs tuned to posterior motion direction (pDSGCs) in mice of both sexes can be transiently sensitized by prior stimuli. Notably, distinct sensitization patterns are found in dorsal and ventral pDSGCs. Although responses of both dorsal and ventral pDSGCs to dark stimuli (Off responses) are sensitized, only dorsal cells show sensitization of responses to bright stimuli (On responses). Visual stimulation to the dorsal retina potentiates a sustained excitatory input from Off bipolar cells, leading to tonic depolarization of pDSGCs. Such tonic depolarization propagates from the Off to the On dendritic arbor of the pDSGC to sensitize its On response. We also identified a previously overlooked feature of DSGC dendritic architecture that can support dendritic integration between On and Off dendritic layers bypassing the soma. By contrast, ventral pDSGCs lack a sensitized tonic depolarization and thus do not exhibit sensitization of their On responses. Our results highlight a topographic difference in Off bipolar cell inputs underlying divergent sensitization patterns of dorsal and ventral pDSGCs. Moreover, substantial crossovers between dendritic layers of On-Off DSGCs suggest an interactive dendritic algorithm for processing On and Off signals before they reach the soma.Significance StatementVisual neuronal responses are dynamically influenced by the prior visual experience. This form of plasticity reflects the efficient coding of the naturalistic environment by the visual system. We found that a class of retinal output neurons, On-Off direction-selective ganglion cells, transiently increase their responsiveness after visual stimulation. Cells located in dorsal and ventral retina exhibit distinct sensitization patterns due to different adaptive properties of Off bipolar cell signaling. A previously overlooked dendritic morphological feature of the On-Off direction-selective ganglion cell is implicated in the crosstalk between On and Off pathways during sensitization. Together, these findings uncover a topographic difference in the adaptive encoding of upper and lower visual fields and the underlying neural mechanism in the dorsal and ventral retina.

Gain control by sparse, ultra-slow glycinergic synapses.

In the retina, ON starburst amacrine cells (SACs) play a crucial role in the direction-selective circuit, but the sources of inhibition that shape their response properties remain unclear. Previous studies demonstrate that ∼95% of their inhibitory synapses are GABAergic, yet we find that the light-evoked inhibitory currents measured in SACs are predominantly glycinergic. Glycinergic inhibition is extremely slow, relying on non-canonical glycine receptors containing α4 subunits, and is driven by both the ON and OFF retinal pathways. These attributes enable glycine inputs to summate and effectively control the output gain of SACs, expanding the range over which they compute direction. Serial electron microscopic reconstructions reveal three specific types of ON and OFF narrow-field amacrine cells as the presumptive sources of glycinergic inhibition. Together, these results establish an unexpected role for specific glycinergic amacrine cells in the retinal computation of stimulus direction by SACs.

Retinal horizontal cells use different synaptic sites for global feedforward and local feedback signaling.

In the outer plexiform layer (OPL) of the mammalian retina, cone photoreceptors (cones) provide input to more than a dozen types of cone bipolar cells (CBCs). In the mouse, this transmission is modulated by a single horizontal cell (HC) type. HCs perform global signaling within their laterally coupled network but also provide local, cone-specific feedback. However, it is unknown how HCs provide local feedback to cones at the same time as global forward signaling to CBCs and where the underlying synapses are located. To assess how HCs simultaneously perform different modes of signaling, we reconstructed the dendritic trees of five HCs as well as cone axon terminals and CBC dendrites in a serial block-face electron microscopy volume and analyzed their connectivity. In addition to the fine HC dendritic tips invaginating cone axon terminals, we also identified "bulbs," short segments of increased dendritic diameter on the primary dendrites of HCs. These bulbs are in an OPL stratum well below the cone axon terminal base and make contacts with other HCs and CBCs. Our results from immunolabeling, electron microscopy, and glutamate imaging suggest that HC bulbs represent GABAergic synapses that do not receive any direct photoreceptor input. Together, our data suggest the existence of two synaptic strata in the mouse OPL, spatially separating cone-specific feedback and feedforward signaling to CBCs. A biophysical model of a HC dendritic branch and voltage imaging support the hypothesis that this spatial arrangement of synaptic contacts allows for simultaneous local feedback and global feedforward signaling by HCs.

Clinical data to be used as a foundation to combat Covid-19 vaccine hesitancy.

The coronavirus has become the paramount subject in peoples' lives, affecting and disrupting virtually every aspect of society, as the pandemic casts a shadow over the world. The facts, myths, and conspiracy theories centered on the Covid-19 pandemic have dominated social media accounts, local and national newspapers, as well as television programs. Strategies need to be evolved to counter Covid-19 vaccine hesitancy and mitigate health disparities in at-risk populations. Overcoming misinformation and distrust will require an interdisciplinary approach to deal with Covid-19. The purpose of this review is to offer a factual basis to all healthcare providers to assist in framing strategies to mitigate vaccine hesitancy and achieve herd immunity to combat the deadly Covid-19 pandemic. First an overview of the discovery of the viruses and their molecular structures will be presented. Secondly, a historical perspective is offered, comparing the differences between the 1918 flu pandemic and the current covid-19 pandemic. Lastly, an overview for proposed techniques and methods to counter and or mitigate covid-19 vaccine misinformation that may be used by an interdisciplinary team will be offered narratively and graphically.

Cholinergic feedback to bipolar cells contributes to motion detection in the mouse retina.

Retinal bipolar cells are second-order neurons that transmit basic features of the visual scene to postsynaptic partners. However, their contribution to motion detection has not been fully appreciated. Here, we demonstrate that cholinergic feedback from starburst amacrine cells (SACs) to certain presynaptic bipolar cells via alpha-7 nicotinic acetylcholine receptors (α7-nAChRs) promotes direction-selective signaling. Patch clamp recordings reveal that distinct bipolar cell types making synapses at proximal SAC dendrites also express α7-nAChRs, producing directionally skewed excitatory inputs. Asymmetric SAC excitation contributes to motion detection in On-Off direction-selective ganglion cells (On-Off DSGCs), predicted by computational modeling of SAC dendrites and supported by patch clamp recordings from On-Off DSGCs when bipolar cell α7-nAChRs is eliminated pharmacologically or by conditional knockout. Altogether, these results show that cholinergic feedback to bipolar cells enhances direction-selective signaling in postsynaptic SACs and DSGCs, illustrating how bipolar cells provide a scaffold for postsynaptic microcircuits to cooperatively enhance retinal motion detection.

New-Onset Seizures in Three COVID-19 Patients: A Case Series.

SUMMARY: Neurological manifestations of coronavirus disease 2019 most commonly present in severe cases and range from mild complications, such as headache and dizziness, to severe complications, such as encephalopathy and acute cerebrovascular disease. Seizures, however, are an underreported neurological manifestation of this disease. We present three critically ill coronavirus disease 2019 patients with EEG monitoring who developed new-onset seizures and encephalopathy up to three-and-a-half weeks after symptom onset. There are several speculated etiologies for the development of new-onset seizures; however, the pathogenic mechanism remains unknown. Testing of coronavirus disease 2019 in the cerebrospinal fluid in addition to extensive research on neurological manifestations is warranted.

Preserving inhibition with a disinhibitory microcircuit in the retina.

Previously, we found that in the mammalian retina, inhibitory inputs onto starburst amacrine cells (SACs) are required for robust direction selectivity of On-Off direction-selective ganglion cells (On-Off DSGCs) against noisy backgrounds (Chen et al., 2016). However, the source of the inhibitory inputs to SACs and how this inhibition confers noise resilience of DSGCs are unknown. Here, we show that when visual noise is present in the background, the motion-evoked inhibition to an On-Off DSGC is preserved by a disinhibitory motif consisting of a serially connected network of neighboring SACs presynaptic to the DSGC. This preservation of inhibition by a disinhibitory motif arises from the interaction between visually evoked network dynamics and short-term synaptic plasticity at the SAC-DSGC synapse. Although the disinhibitory microcircuit is well studied for its disinhibitory function in brain circuits, our results highlight the algorithmic flexibility of this motif beyond disinhibition due to the mutual influence between network and synaptic plasticity mechanisms.

A Rare Case of Disseminated Coccidioidomycosis Presenting as Brachial Plexopathy.

Coccidioidomycosis, a fungal infection caused by inhaling spores of Coccidioides immitis/posadasii, is endemic to the southwestern states of the United States, Northern Mexico and some parts of Central and South America. It is primarily a pulmonary infection with less than 0.5% of symptomatic cases showing dissemination. Skin, lymph nodes and bone are the commonest sites. Neurological involvement is rare and commonly presents as strokes, abscesses or meningoencephalitis. We present the case of a previously healthy 23-year-old African American male, presented with a four-month history of progressive right upper extremity weakness that initially started with right shoulder pain followed by worsening weakness and loss of muscle mass. Electromyography (EMG) demonstrated right brachial plexopathy with moderate-to-severe active denervation changes. MRI cervical spine revealed a 9-cm contrast enhancing extradural mass extending through the neural foramen from C4-T1 roots and forming a 4-cm right apical lung mass subsequently seen on MRI of the brachial plexus. All trunks, divisions and cords were thickened, hyperintense and showed contrast enhancement on MRI. Neuromuscular ultrasound (NUS) demonstrated enlargement of peripheral nerves. Differentials prior to biopsy of the mass ranged from neurofibromas to pancoast lung tumors. Coccidioidomycosis did not figure on the initial list of differentials. Patient underwent subsequent biopsy of the extradural and lung masses that showed coccidiodes. Serum coccidioides antibody titers were elevated. The patient was treated with high-dose intravenous fluconazole and aggressive mass debridement. His weakness improved on four months follow-up evaluation with significant resolution of EMG abnormalities and decreased swelling on NUS.

Bayesian inference for biophysical neuron models enables stimulus optimization for retinal neuroprosthetics.

While multicompartment models have long been used to study the biophysics of neurons, it is still challenging to infer the parameters of such models from data including uncertainty estimates. Here, we performed Bayesian inference for the parameters of detailed neuron models of a photoreceptor and an OFF- and an ON-cone bipolar cell from the mouse retina based on two-photon imaging data. We obtained multivariate posterior distributions specifying plausible parameter ranges consistent with the data and allowing to identify parameters poorly constrained by the data. To demonstrate the potential of such mechanistic data-driven neuron models, we created a simulation environment for external electrical stimulation of the retina and optimized stimulus waveforms to target OFF- and ON-cone bipolar cells, a current major problem of retinal neuroprosthetics.

Mitigating the opioid crisis for the lower extremity provider opioid stewardship programs.

Opioids are an effective form of analgesia for pain treatment. Over prescribing of opioids agents have becom;1;e detrimental to the United States' public health. One of the most difficult challenges for any prescriber is to balance the potential benefits versus the potential risks of opioid prescribing. Addressing the opioid crisis requires an interprofessional team approach. The utilization of an opioid stewardship program provides the necessary frame work to identify gaps in the in quality and development in the implementation of a change of long standing opioid culture and practice. These programs address opioid prescribing, treatment for opioid use disorder, educational initiatives, and the use of information technology. A few acronyms have been created to assist providers to guide them when prescribing opioids. The purpose of this article is to explore the central theme of responsible opioid pain management. It will introduce, define, and defend with clinical base evidence a proposed acronym "MORPHINE" to assist and help shape prescription opioid strategies used for lower extremity pain. Implications for practicing lower extremity providers need to acknowledge the potential harm that prescribing opioids may cause to their patients. Opioid stewardship principles should become a priority in podiatric medicine and podiatric surgery.

Light-evoked glutamate transporter EAAT5 activation coordinates with conventional feedback inhibition to control rod bipolar cell output.

In the retina, modulation of the amplitude of dim visual signals primarily occurs at axon terminals of rod bipolar cells (RBCs). GABA and glycine inhibitory neurotransmitter receptors and the excitatory amino acid transporter 5 (EAAT5) modulate the RBC output. EAATs clear glutamate from the synapse, but they also have a glutamate-gated chloride conductance. EAAT5 acts primarily as an inhibitory glutamate-gated chloride channel. The relative role of visually evoked EAAT5 inhibition compared with GABA and glycine inhibition has not been addressed. In this study, we determine the contribution of EAAT5-mediated inhibition onto RBCs in response to light stimuli in mouse retinal slices. We find differences and similarities in the two forms of inhibition. Our results show that GABA and glycine mediate nearly all lateral inhibition onto RBCs, as EAAT5 is solely a mediator of RBC feedback inhibition. We also find that EAAT5 and conventional GABA inhibition both contribute to feedback inhibition at all stimulus intensities. Finally, our in silico modeling compares and contrasts EAAT5-mediated to GABA- and glycine-mediated feedback inhibition. Both forms of inhibition have a substantial impact on synaptic transmission to the postsynaptic AII amacrine cell. Our results suggest that the late phase EAAT5 inhibition acts with the early phase conventional, reciprocal GABA inhibition to modulate the rod signaling pathway between rod bipolar cells and their downstream synaptic targets.NEW & NOTEWORTHY Excitatory amino acid transporter 5 (EAAT5) glutamate transporters have a chloride channel that is strongly activated by glutamate, which modulates excitatory signaling. We found that EAAT5 is a major contributor to feedback inhibition on rod bipolar cells. Inhibition to rod bipolar cells is also mediated by GABA and glycine. GABA and glycine mediate the early phase of feedback inhibition, and EAAT5 mediates a more delayed inhibition. Together, inhibitory transmitters and EAAT5 coordinate to mediate feedback inhibition, controlling neuronal output.

US Food and Drug Administration Black Box Warnings.

Podiatric Physicians have an ethical obligation to prescribe responsibly and cautiously to diminish and minimize the growth of drug adverse effects. Clinicians who prescribe, dispense, and administer medications must be vigilant in continually reviewing new Black Box Warnings for medications they use for their patients. The safe and appropriate selection of medications and prescribing strategies are presented. First, the concept and process for these FDA black box warnings are introduced. Then, to enrich the podiatric physician's body of knowledge, several FDA boxed warnings from 27 selected drug products that may be prescribed by podiatric physicians are presented graphically as a table. Finally, strategies for safe prescribing of these drugs with boxed warnings are presented.